The medical letter on drugs and therapeutics may 25 2015

The Medical Letter

®

on Drugs and Therapeutics
Objective Drug Reviews Since 1959
Volume 57

ISSUE
ISSUE
No.

1433
1469
Volume 56

May 25, 2015

IN THIS ISSUE

Ivabradine (Corlanor) for Heart Failure ...................................................................... p 75
Fluticasone Furoate (Arnuity Ellipta) for Asthma ........................................................ p 76
Ceftazidime/Avibactam (Avycaz) — A New Intravenous Antibiotic ................................ p 79
New Website and App Announcement ....................................................................... p 80

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The Medical Letter

®

on Drugs and Therapeutics
Objective Drug Reviews Since 1959
Volume 57

ISSUE

ISSUE No.

1433
1469
Volume 56

▶

May 25, 2015
Take CME Exams
ALSO IN THIS ISSUE

Fluticasone Furoate (Arnuity Ellipta) for Asthma ................................................................p 76
Ceftazidime/Avibactam (Avycaz) — A New Intravenous Antibiotic ....................................p 79
New Website and App Announcement ..................................................................................p 80

Ivabradine (Corlanor) for Heart
Failure

The FDA has approved ivabradine (Corlanor – Amgen)
to reduce the risk of hospitalization for worsening heart
failure in adults with stable, symptomatic chronic heart
failure with left ventricular ejection fraction (LVEF) ≤35%
who are in sinus rhythm with a resting heart rate ≥70
beats per minute and who are on maximum tolerated
doses of beta blockers or have a contraindication
to beta blocker use. Ivabradine has been available
internationally for years as Procoralan and Corlentor
for treatment of stable angina and heart failure.
Pronunciation Key
Ivabradine: eye vab’ ra deen
Corlanor: kor’ lan or

STANDARD TREATMENT — All patients with heart
failure with reduced ejection fraction (LVEF ≤40%)
generally should take both an angiotensin-converting

enzyme (ACE) inhibitor and a beta blocker, and if volume
overloaded, a diuretic as well. An angiotensin receptor
blocker (ARB) is recommended for patients who cannot
tolerate an ACE inhibitor. In patients with symptomatic
heart failure and ejection fraction ≤35%, or reduced
ejection fraction after a myocardial infarction, addition
of an aldosterone antagonist can reduce the risk of
hospitalization or death. Addition of hydralazine/
isosorbide dinitrate (BiDil) to standard therapy has
been shown to reduce symptoms and mortality in
black patients with NYHA class III-IV heart failure
with reduced ejection fraction. Digoxin can decrease
symptoms and lower the rate of hospitalization for
heart failure, but it does not reduce mortality.1
MECHANISM OF ACTION — Ivabradine slows heart
rate by inhibiting the cardiac pacemaker If current.
It has no effect on ventricular repolarization or
myocardial contractility.

Table 1. Pharmacology
Class

Hyperpolarization-activated cyclic nucleotidegated channel blocker

Formulation
Route
Tmax
Metabolism
Elimination

5-, 7.5-mg tablets (5-mg tabs are scored)
Oral
~1 hr
Primarily hepatic via CYP3A4
Urine (~4% unchanged); metabolites in
feces and urine
~6 hours

Half-life

CLINICAL STUDIES — Approval of Corlanor was based
on a randomized, double-blind, placebo-controlled
trial (SHIFT) in 6558 adults with NYHA class II-IV
heart failure, LVEF ≤35%, and a resting heart rate
≥70 bpm who had been hospitalized for heart failure
within 12 months before study entry. In addition to
their background treatment, which generally included
a beta blocker, patients received either ivabradine
5 mg twice daily, which could be increased to 7.5 mg
twice daily or decreased to 2.5 mg twice daily
to maintain a resting heart rate between 50 and
60 bpm, or placebo. After a median follow-up of
22.9 months, a composite of hospitalization for
worsening heart failure or cardiovascular death, the
primary endpoint, occurred in significantly fewer
patients taking ivabradine than taking placebo (24%
vs 29%). Ivabradine significantly reduced the risk
of hospitalization for worsening heart failure (16%
vs 21% with placebo) and death due to heart failure
(3% vs 5%), but it did not have a significant effect on

cardiovascular death (14% vs 15%).2
In a trial in 10,917 patients with coronary artery disease and stable heart failure (BEAUTIFUL), ivabradine
did not significantly affect the primary composite
endpoint of cardiovascular death, hospitalization
for acute MI, or hospitalization for new-onset or
worsening heart failure, compared to placebo.3
75

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In another placebo-controlled trial in 19,102 patients
who had coronary artery disease without clinically
evident heart failure (SIGNIFY), ivabradine also did not
significantly affect the primary endpoint, a composite
of cardiovascular death or nonfatal MI. Moreover, a
prespecified subgroup analysis in patients with more
than minimal angina pectoris found a significantly
higher incidence of the primary endpoint with
ivabradine (7.6% vs 6.5% with placebo).4
ADVERSE EFFECTS — The most common adverse
effects of ivabradine in the SHIFT trial were
bradycardia, hypertension, atrial fibrillation, and
visual disturbances (transient increases in brightness)
caused by inhibition of electric currents in the retina.
These disturbances, called phosphenes, generally

occurred within the first 2 months of ivabradine
treatment; most were of mild to moderate intensity
and resolved during or after treatment.
Syncope, hypotension, angioedema, erythema, rash,
pruritus, urticaria, vertigo, diplopia, and visual impairment have also been reported.
Table 2. Contraindications to Ivabradine

▶
▶
▶
▶
▶
▶
▶

Acute decompensated heart failure
Blood pressure <90/50 mmHg
Sick sinus syndrome, sinoatrial block, or 3rd degree AV block,
unless a functioning demand pacemaker is present
Resting heart rate <60 bpm prior to treatment
Severe hepatic impairment (Child-Pugh C)
Pacemaker dependence
Concomitant use of strong CYP3A4 inhibitors

PREGNANCY — Fetal toxicity and cardiac teratogenic
effects have occurred in animal studies with ivabradine.
Women of childbearing age should use an effective
form of contraception while taking the drug. Pregnant
women taking ivabradine should be monitored for
bradycardia, destabilization of heart failure, and preterm birth (in the third trimester). Breastfeeding is not

recommended while taking ivabradine.
DRUG INTERACTIONS — Ivabradine is a substrate of
CYP3A4; concurrent use with strong CYP3A4 inhibitors
is contraindicated and concurrent use with CYP3A4
inducers or moderate CYP3A4 inhibitors should be
avoided.5
DOSAGE, ADMINISTRATION, AND COST — The
recommended starting dosage of Corlanor is 5 mg
twice daily with meals. After 2 weeks, if the patient’s
heart rate is within the target range of 50-60 bpm,
the starting dosage should be continued. If the heart
rate is >60 bpm, the dose should be increased by
2.5 mg twice daily up to a maximum of 7.5 mg twice
76

Vol. 57 (1469)

May 25, 2015

daily. If the heart rate is <50 bpm or the patient has
signs and symptoms of bradycardia, the dose should
be decreased by 2.5 mg twice daily; if the patient is
already taking 2.5 mg twice daily, the drug should be
discontinued. The cost of 30 days' treatment with
Corlanor 5 mg twice daily is $375.6
CONCLUSION — Reducing heart rate with ivabradine
(Corlanor) might prevent hospitalization for worsening
heart failure in some patients, but it has not been
shown to reduce cardiovascular mortality. In one
study in patients with stable coronary artery disease

without heart failure, use of ivabradine did not improve
outcomes and was associated with an increased risk
of myocardial infarction or cardiovascular death in
patients with angina. ■
1. Drugs for chronic heart failure. Med Lett Drugs Ther 2015; 57:9.
2. K Swedberg et al. Ivabradine and outcomes in chronic heart
failure (SHIFT): a randomised placebo-controlled study. Lancet
2010; 376:875.
3. K Fox et al. Ivabradine for patients with stable coronary artery
disease and left-ventricular systolic dysfunction (BEAUTIFUL):
a randomised, double-blind, placebo-controlled trial. Lancet
2008; 372:807.
4. K Fox et al. Ivabradine in stable coronary artery disease without
clinical heart failure. N Engl J Med 2014; 371:1091.
5. Inhibitors and inducers of CYP enzymes and P-glycoprotein.
Med Lett Drugs Ther 2013; 55:e44.
6. Approximate WAC. WAC = wholesaler acquisition cost or manufacturer’s published price to wholesalers; WAC represents a
published catalogue or list price and may not represent an actual transactional price. Source: AnalySource® Monthly. May
5, 2015. Reprinted with permission by First Databank, Inc. All
rights reserved. ©2015. www.fdbhealth.com/policies/drugpricing-policy.

▶

Fluticasone Furoate (Arnuity
Ellipta) for Asthma

The FDA has approved Arnuity Ellipta (GSK), a singleagent inhaler containing the corticosteroid fluticasone
furoate, for once-daily maintenance treatment of
asthma in patients ≥12 years old. Fluticasone furoate
is also available in combination with the long-acting

beta2-agonist vilanterol as Breo Ellipta for treatment
of asthma and COPD.1
Pronunciation Key
Fluticasone furoate: floo tik’ a sone fure’ oh ate
Arnuity Ellipta: ar new’ i tee ee lip’ ta

MAINTENANCE TREATMENT — An inhaled corticosteroid is the most effective long-term treatment for
control of mild, moderate, or severe persistent asthma.
In randomized controlled trials, inhaled corticosteroids have been significantly more effective than
long-acting beta2-agonists, leukotriene modifiers,
cromolyn, or theophylline in improving pulmonary


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®

function, preventing symptoms and exacerbations,
reducing the need for emergency department
treatment, and decreasing deaths due to asthma.2 For
patients who remain symptomatic despite compliance
and good inhalation technique, addition of a longacting beta2-agonist is recommended. Patients with
more severe disease may need higher doses of inhaled
corticosteroids.3
Table 1. Pharmacology
Class

Corticosteroid

Formulation

Dry powder inhaler (100, 200 mcg/inh)

Route

Oral inhalation

Tmax

0.5-1 hour

Metabolism

Hepatic via CYP3A4

Half-life

24 hours

Elimination

Primarily in feces as parent drug and
metabolite, minimally in urine

FLUTICASONE FUROATE VS PROPIONATE —
Compared to fluticasone propionate, which is available alone as Flovent Diskus and Flovent HFA for
treatment of asthma and in combination with the
long-acting beta2-agonist salmeterol as Advair Diskus
and Advair HFA for treatment of asthma and COPD,
fluticasone furoate has demonstrated a higher binding

affinity for the glucocorticoid receptor in vitro and
inhibited inflammatory mediators more potently in an
in vivo model.4 Whether these differences are clinically
significant is not known.
CLINICAL STUDIES — The efficacy of fluticasone
furoate was evaluated in four randomized, doubleblind trials in patients with asthma. Mean change from
baseline in trough forced expiratory volume in 1 second
(FEV1) was a primary endpoint in all four studies (see
Table 2).5-8
In one trial in 219 patients with moderate to severe
asthma not controlled on a mid- to high-dose inhaled
corticosteroid, the mean increase in trough FEV1 from
baseline at week 24 was 208 mL with fluticasone
furoate 100 mcg once daily and 284 mL with
fluticasone furoate 200 mcg once daily.5
A trial in 343 patients with asthma not controlled on
inhaled corticosteroid therapy randomized patients
to fluticasone furoate 100 mcg once daily, fluticasone
propionate 250 mcg twice daily, or placebo. After 24
weeks, the mean change from baseline in trough FEV1
was 161 mL with fluticasone furoate and 159 mL with
fluticasone propionate, both significant differences
compared to placebo (15 mL).6
In a 12-week study, 609 patients with persistent
asthma using a low- to mid-dose inhaled cortico-

Vol. 57 (1469)

May 25, 2015

Table 2. Some Fluticasone Furoate Clinical Trials
Study Design

Regimen

Trough
FEV1 (mL)1

A Woodcock et al.
24 weeks (n=219)

FF 100 mcg once/d
FF 200 mcg once/d

208
284

J Lötvall et al.
24 weeks (n=343)

FF 100 mcg once/d
FP 250 mcg bid
Placebo

161
159
15

ER Bleeker et al.
12 weeks (n=609)

FF 100 mcg once/d
FF/VI 100/25 mcg once/d
Placebo

332
368
196

PM O’Byrne et al.
24 weeks (n=586)

FF/VI 200/25 mcg once/d
FF 200 mcg once/d
FP 500 mcg bid

394
2012
183

FF = fluticasone furoate; FP = fluticasone propionate; VI = vilanterol
1. Mean change from baseline in trough FEV1.
2. Fluticasone furoate was noninferior to fluticasone propionate in improving
trough FEV1 from baseline.

steroid were randomized to receive once-daily
fluticasone furoate 100 mcg, fluticasone furoate/
vilanterol 100/25 mcg, or placebo. Trough FEV1 was
significantly improved in patients taking fluticasone
furoate (332 mL) or fluticasone furoate/vilanterol (368

mL), compared to those taking placebo (196 mL).
Change from baseline in serial weighted mean FEV1, a
coprimary endpoint, was also significantly greater in
patients who received fluticasone furoate or fluticasone
furoate/vilanterol than in those taking placebo.7
In another study, 586 patients with moderate to
severe persistent asthma not controlled on a mid- to
high-dose inhaled corticosteroid were randomized
to receive fluticasone furoate/vilanterol 200/25 mcg
once daily, fluticasone furoate 200 mcg once daily,
or fluticasone propionate 500 mcg twice daily for
24 weeks. Fluticasone furoate was noninferior to
fluticasone propionate in improving trough FEV1
(201 mL vs 183 mL). Weighted mean FEV1, a coprimary
endpoint, improved from baseline at week 24 with
both fluticasone furoate (328 mL) and fluticasone
propionate (258 mL).8
ADVERSE EFFECTS — In clinical trials with fluticasone
furoate, common adverse effects (reported in ≥5% of
subjects and more frequently than with placebo)
included upper respiratory tract infection, nasopharyngitis, headache, and bronchitis.
Local adverse effects of inhaled corticosteroids
include oral candidiasis (thrush), dysphonia, reflex
cough, and bronchospasm. Cataracts, glaucoma,
and changes in bone density can occur with high
doses of inhaled corticosteroids. Clinically relevant
effects on hypothalamic-pituitary-adrenal (HPA) axis
function generally do not occur with low- or mediumdose inhaled corticosteroids; patients who require
treatment with high doses should be monitored for
77

The Medical Letter

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Vol. 57 (1469)

May 25, 2015

Table 3. Some Inhaled Corticosteroids for Maintenance Treatment of Asthma
Drugs

Some Available
Formulations

Usual
Adult Dosage1

Usual
Pediatric Dosage1

HFA MDI (120 inh/unit)
40, 80 mcg/inh

40-320 mcg bid

5-11 yrs: 40-80 mcg
bid

DPI (60, 120 inh/unit)
90, 180 mcg/inh
HFA MDI (60 inh/unit)
80, 160 mcg/inh
HFA MDI (60, 120 inh/unit)
80 mcg/inh
DPI (14, 30 inh/unit)
100, 200 mcg/blister

180-720 mcg bid

6-17 yrs: 180-360 mcg
bid
≥12 yrs: 80-320 mcg
bid
6-11 yrs: 80-160 mcg
bid
≥12 yrs: 100-200 mcg
once/d

Cost2

Inhaled Corticosteroids
Beclomethasone
dipropionate – QVAR (Teva)
Budesonide –
Pulmicort Flexhaler
(AstraZeneca)
Ciclesonide –
Alvesco (Sunovion)

Flunisolide –
Aerospan HFA (Meda)
Fluticasone furoate –
Arnuity Ellipta (GSK)
Fluticasone propionate –
Flovent Diskus (GSK)
Flovent HFA (GSK)
Mometasone furoate –
Asmanex Twisthaler (Merck)

160-320 mcg bid
100-200 mcg once/d

DPI (60 inh/unit)
50, 100, 250 mcg/blister
HFA MDI (120 inh/unit)
44, 110, 220 mcg/inh

100-1000 mcg bid

DPI (30, 60, 120 inh/unit)
110, 220 mcg/inh

220-440 mcg
once/d in the evening
or 220-440 mcg bid
200-400 mcg bid

Asmanex HFA (Merck)

HFA MDI (120 inh/unit)
100, 200 mcg/inh
Inhaled Corticosteroid/Long-Acting Beta2-Agonist Combinations
Budesonide/formoterol –
Symbicort (AstraZeneca)

80-320 mcg bid

HFA MDI (60, 120 inh/unit)
80, 160 mcg/4.5 mcg per inh

Fluticasone furoate/vilanterol –
Breo Ellipta (GSK)

DPI (14, 30 inh/unit)
100, 200 mcg/25 mcg per inh
Fluticasone propionate/salmeterol –
Advair Diskus (GSK)
DPI (60 inh/unit)
100, 250, 500 mcg/50 mcg per
blister
Advair HFA (GSK)
HFA MDI (60, 120 inh/unit)
45, 115, 230 mcg/21 mcg per inh
Mometasone/formoterol –
Dulera (Merck)
HFA MDI (60, 120 inh/unit)
100, 200 mcg/5 mcg per inh

88-880 mcg bid

4-11 yrs: 50-100 mcg
bid
4-11 yrs: 88 mcg bid

$139.503

183.80

208.30
155.00
130.40
144.00
144.00

4-11 yrs: 110 mcg
once/d in the evening

156.10

≥12 yrs: 200-400 mcg
bid

156.10

2 inhalations bid

≥12 yrs: 2 inhalations bid

240.30

1 inhalation once/d

Not approved for patients
<18 years old

281.10

1 inhalation bid

239.80

2 inhalations bid

4-11 yrs: 1 inhalation
(100/50 mcg) bid
≥12 yrs: 1 inhalation bid
≥12 yrs: 2 inhalations bid

239.80

2 inhalations bid

≥12 yrs: 2 inhalations bid

256.50

inh = inhalation; HFA = hydrofluoroalkane; MDI = metered-dose inhaler; DPI = dry powder inhaler
1. For most inhaled corticosteroids, the dose is based on asthma severity and/or prior asthma therapy. See package insert for specific dosing instructions.
2. Approximate WAC for 30 days’ treatment at the lowest usual adult dosage. WAC = wholesaler acquisition cost or manufacturer’s published price to wholesalers;

WAC represents a published catalogue or list price and may not represent an actual transactional price. Source: AnalySource® Monthly. May 5, 2015. Reprinted
with permission by First Databank, Inc. All rights reserved. ©2015. www.fdbhealth.com/policies/drug-pricing-policy.
3. Cost of a 60-day supply at the lowest usual adult dosage.

HPA axis suppression. Regular administration of
inhaled corticosteroids may reduce growth slightly
during the first year of treatment, especially in
prepubertal patients.
PREGNANCY — Fluticasone furoate is classified as
category C (corticosteroids are teratogenic in animals;
no adequate studies in women) for use during
pregnancy.
DRUG INTERACTIONS — Fluticasone furoate is a
substrate of CYP3A4. The drug should be used
cautiously with strong CYP3A4 inhibitors, such as
clarithromycin9; coadministration with ketoconazole,
a strong inhibitor of CYP3A4, increased the AUC of
fluticasone furoate by 36%.10
78

DOSAGE AND ADMINISTRATION — In patients not already taking an inhaled corticosteroid, the usual starting
dosage of Arnuity Ellipta is one 100-mcg inhalation once
daily. After 2 weeks, the dosage may be increased to
200 mcg once daily if needed. For patients already taking
an inhaled corticosteroid, the starting dose should be
based on previous asthma therapy and disease severity.
The AUC of fluticasone furoate increased up to 3-fold in
patients with hepatic impairment.
Each Arnuity Ellipta dry powder inhaler contains 30
doses of the drug and has a dose counter to track the

number of doses that have been used. Opening the inhaler cover readies a dose for inhalation and causes the
counter to count down by 1. Closing the cover without


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®

inhaling the medication wastes that dose, which will
remain in the device but will no longer be usable.
CONCLUSION — Once-daily inhalation of fluticasone
furoate (Arnuity Ellipta) has improved lung function in
patients with moderate to severe persistent asthma.
Its efficacy appears to be similar to that of twice-daily
fluticasone propionate (Flovent), and it costs about
the same. ■
1. Breo Ellipta: an inhaled fluticasone/vilanterol combination for
COPD. Med Lett Drugs Ther 2013; 55:69.
2. National Heart, Lung and Blood Institute. National Asthma Education and Prevention Program (NAEPP). Guidelines for the diagnosis and management of asthma (EPR-3). Full Report 2007.
Available at www.nhlbi.nih.gov/guidelines/asthma/index.htm.
Accessed May 14, 2015.
3. Drugs for asthma and COPD. Treat Guidel Med Lett 2013; 11:75.
4. M Salter et al. Pharmacological properties of the enhancedaffinity glucocorticoid fluticasone furoate in vitro and in an in
vivo model of respiratory inflammatory disease. Am J Physiol
Lung Cell Mol Physiol 2007; 293:L660.
5. A Woodcock et al. Efficacy and safety of fluticasone furoate 100
μg and 200 μg once daily in the treatment of moderate-severe
asthma in adults and adolescents: a 24-week randomised
study. BMC Pulm Med 2014; 14:113.
6. J Lötvall et al. Efficacy and safety of fluticasone furoate 100 μg

once-daily in patients with persistent asthma: a 24-week placebo
and active-controlled randomised trial. Respir Med 2014; 108:41.
7. ER Bleecker et al. Fluticasone furoate-vilanterol 100-25 mcg
compared with fluticasone furoate 100 mcg in asthma: a randomized trial. J Allergy Clin Immunol Pract 2014; 2:553.
8. PM O’Byrne et al. Once-daily fluticasone furoate alone or combined
with vilanterol in persistent asthma. Eur Respir J 2014; 43:773.
9. Inhibitors and inducers of CYP enzymes and P-glycoprotein.
Med Lett Drugs Ther 2013; 55:e44.
10. R Kempsford et al. The effect of ketoconazole on the pharmacokinetics and pharmacodynamics of inhaled fluticasone
furoate and vilanterol trifenatate in healthy subjects. Br J Clin
Pharmacol 2013; 75:1478.

▶

Ceftazidime/Avibactam (Avycaz) —
A New Intravenous Antibiotic

The FDA has approved ceftazidime/avibactam
(Avycaz – Actavis) for IV treatment of complicated
urinary tract and intra-abdominal infections in adults
who have limited or no other treatment options.
Ceftolozane/tazobactam (Zerbaxa – Cubist), another
cephalosporin/beta-lactamase inhibitor combination,
was approved in 2014.1
Pronunciation Key
Ceftazidime: sef taz' i deem
Avibactam: ay" vee bak' tam
Avycaz: a' vee kaz

SPECTRUM — Ceftazidime is a third-generation

cephalosporin with activity against enteric gramnegative bacilli, but minimal to no activity against
anaerobic or gram-positive pathogens. Avibactam
is a non-beta-lactam beta-lactamase inhibitor that
inhibits the activity of enyzmes in Ambler classes A
and C, and some in class D.

Vol. 57 (1469)

May 25, 2015

Table 1. FDA-Approved Indications for Avycaz1

▶ Complicated

urinary tract infections, including pyelonephritis,
caused by: Escherichia coli, Klebsiella pneumoniae, Citrobacter
koseri, Enterobacter aerogenes, Enterobacter cloacae, Citrobacter
freundii, Proteus spp., and/or Pseudomonas aeruginosa
▶ Complicated intra-abdominal infections2 caused by: Escherichia
coli, Klebsiella pneumoniae, Proteus mirabilis, Providencia
stuartii, Enterobacter cloacae, Klebsiella oxytoca, and/or
Pseudomonas aeruginosa
1. Use should be restricted to patients who have limited or no alternative
treatment options.
2. In combination with metronidazole.

The addition of avibactam improves ceftazidime's
activity against Pseudomonas aeruginosa and many
extended-spectrum beta-lactamase (ESBL)-producing
gram-negative pathogens. Ceftazidime/avibactam

is the first beta-lactam/beta-lactamase inhibitor
combination to have activity against some
carbapenem-resistant Enterobacteriaceae, including
those that produce Klebsiella pneumoniae carbapenemase (KPC), the most common carbapenemase in
the US. The combination is not active against organisms
that produce metallo-beta-lactamases.2
STANDARD TREATMENT — Complicated urinary tract
infections occur in patients with comorbid conditions,
such as indwelling urinary catheters or anatomic or
functional abnormalities of the urinary tract, and are
often caused by antibiotic-resistant gram-negative
bacilli (including Escherichia coli, K. pneumoniae,
Proteus mirabilis, and P. aeruginosa) or enterococci.
In hospitalized patients, empiric parenteral treatment
with cefepime, a third-generation cephalosporin such
as ceftriaxone, a fluoroquinolone such as levofloxacin or ciprofloxacin, piperacillin/tazobactam, or a
carbapenem is generally recommended.3
Most intra-abdominal infections, such as cholangitis
and diverticulitis, are caused by enteric gram-negative
organisms (most commonly E. coli); enterococci and
anaerobes such as B. fragilis are also common pathogens. Many intra-abdominal infections, particularly
abscesses, are polymicrobial. For communityacquired infections of mild to moderate severity, such
as acute appendicitis, monotherapy with ertapenem or
moxifloxacin would be a reasonable choice. In severely
ill patients and in those with prolonged hospitalization,
treatment should include coverage for P. aeruginosa; an
antipseudomonal penicillin (piperacillin/tazobactam)
or carbapenem (imipenem, meropenem, or doripenem)
could be used.3,4
CLINICAL STUDIES — Approval of ceftazidime/

avibactam was based on the established safety and
efficacy of ceftazidime for treatment of complicated
79


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®

Table 2. Pharmacology
Class
Route
Formulation
Usual adult dosage
Dosage in renal
impairment

Metabolism
Excretion
Half-life

Cephalosporin antibiotic/beta-lactamase
inhibitor
Intravenous
2.5-g single-use vials
(2 g ceftazidime/0.5 g avibactam)
2.5 g (infused over 2 hours) every 8 hours
CrCl 31-50 mL/min: 1.25 g every 8 hours
CrCl 16-30 mL/min: 0.94 g every 12 hours
CrCl 6-15 mL/min: 0.94 g every 24 hours

CrCl ≤5 mL/min: 0.94 g every 48 hours
Ceftazidime: none
Avibactam: none
Ceftazidime: urine (80-90% unchanged)
Avibactam: urine (97% unchanged)
Ceftazidime: ~3 hours
Avibactam: ~2.5 hours

urinary tract and intra-abdominal infections, the
activity of avibactam in vitro and in animal studies,
and 2 randomized, active-controlled, phase 2 trials.
One trial in 135 patients with complicated urinary tract
infection compared ceftazidime/avibactam 500/125 mg
every 8 hours with imipenem/cilastatin 500 mg every 6
hours. A favorable microbiological response occurred
in 19 of 27 (70.4%) microbiologically evaluable patients
treated with the ceftazidime combination and in 25 of
35 (71.4%) patients treated with imipenem.5
In another trial, 203 adults with complicated intraabdominal infection requiring surgical intervention were
randomized to ceftazidime/avibactam 2000/500 mg
plus metronidazole 500 mg, or to meropenem 1000 mg,
both given every 8 hours for 5-14 days. The clinical
response in microbiologically evaluable patients was
favorable in 71 of 76 (93.4%) treated with ceftazidime/
avibactam and in 62 of 68 (91.2%) treated with
meropenem.6
ADVERSE EFFECTS — Nausea and vomiting were the
most common adverse effects in the intra-abdominal
infection trial.5 Constipation and anxiety were most
common in the urinary tract infection trial.6 As with

other beta-lactam antibiotics, Clostridium difficileassociated diarrhea and serious hypersensitivity
reactions can occur with ceftazidime/avibactam.
DRUG INTERACTIONS — In vitro, avibactam is
a substrate of OAT1 and OAT3 transporters;
coadministration with the potent OAT inhibitor
probenecid could decrease avibactam elimination and
is not recommended.
PREGNANCY — Avycaz is classified as category B (no
evidence of harm in animals; no adequate studies in
women) for use during pregnancy.

80

Vol. 57 (1469)

May 25, 2015

DOSAGE, ADMINISTRATION, AND COST — The
recommended dosage of Avycaz is 2.5 g (2 g
ceftazidime/0.5 g avibactam), infused intravenously
over 2 hours, every 8 hours. Dosage reductions are
recommended for patients with renal impairment (see
Table 2). When used for treatment of intra-abdominal
infections, addition of metronidazole is needed for
anaerobic coverage. The recommended duration
of treatment is 7-14 days for complicated urinary
tract infections and 5-14 days for complicated intraabdominal infections. One day of treatment costs $855.7
CONCLUSION — Ceftazidime/avibactam (Avycaz) is
the second IV combination of a cephalosporin and
a beta-lactamase inhibitor to become available in

the US. It is the first beta-lactam/beta-lactamase
inhibitor combination to have activity against Klebsiella
pneumoniae carbapenemase (KPC)-producing gramnegative bacilli. Approval of the combination was based
on limited clinical data in patients with complicated
urinary tract or intra-abdominal infections, but it
will likely be used more generally to treat serious
infections caused by KPC-producing and other multidrug resistant pathogens. ■
1. Ceftolozane/tazobactam (Zerbaxa) – a new intravenous antibiotic. Med Lett Drugs Ther 2015; 57:31.
2. GG Zhanel et al. Ceftazidime-avibactam: a novel cephalosporin/
β-lactamase inhibitor combination. Drugs 2013; 73:159.
3. Drugs for bacterial infections. Treat Guidel Med Lett 2013; 11:65.
4. JS Solomkin et al. Diagnosis and management of complicated
intra-abdominal infection in adults and children: guidelines by
the Surgical Infection Society and the Infectious Diseases Society of America. Clin Infect Dis 2010; 50:133.
5. JA Vazquez et al. Efficacy and safety of ceftazidime-avibactam
versus imipenem-cilastatin in the treatment of complicated
urinary tract infections, including acute pyelonephritis, in hospitalized adults: results of a prospective, investigator-blinded,
randomized study. Curr Med Res Opin 2012; 28:1921.
6. C Lucasti et al. Comparative study of the efficacy and safety of
ceftazidime/avibactam plus metronidazole versus meropenem
in the treatment of complicated intra-abdominal infections
in hospitalized adults: results of a randomized, double-blind,
Phase II trial. J Antimicrob Chemother 2013; 68:1183.
7. Approximate WAC of 1 day's treatment with the usual dosage.
WAC = wholesaler acquisition cost or manufacturer’s published
price to wholesalers; WAC represents a published catalogue or
list price and may not represent an actual transactional price.
Source: AnalySource® Monthly. May 5, 2015. Reprinted with
permission by First Databank, Inc. All rights reserved. ©2015.
www.fdbhealth.com/policies/drug-pricing-policy.

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Issue 1469 Questions

(Correspond to questions #101-110 in Comprehensive Exam #72, available July 2015)
6. Compared to fluticasone propionate, fluticasone furoate:
a. is significantly more effective in reducing asthma

exacerbations
b. is significantly more effective in improving trough FEV1
c. has a higher affinity for the glucocorticoid receptor in vitro
d. all of the above

Ivabradine (Corlanor) for Heart Failure
1. Ivabradine:
a. increases myocardial contractility
b. delays ventricular repolarization
c. lowers heart rate
d. all of the above
2. In the SHIFT trial, compared to placebo, ivabradine:
a. reduced the composite of hospitalization for worsening
heart failure or cardiovascular death
b. reduced the number of deaths due to heart failure
c. reduced the number of hospitalizations for worsening
heart failure
d. all of the above

7. Approval of Arnuity Ellipta for treatment of asthma was based
on clinical trials demonstrating that it:
a. reduces mortality
b. reduces the incidence of exacerbations
c. improves FEV1 from baseline
d. all of the above

3. A 66-year-old white man with chronic heart failure treated
for years with an ACE inhibitor and maximum doses of a beta
blocker has recently had ivabradine added to his regimen by his
cardiologist. He comes to you complaining of the sudden onset

of transient visual disturbances characterized by an increase in
brightness. You could tell him that these are probably caused
by:
a. transient ischemic attacks caused by clots migrating from
the carotid artery
b. retinal vasospasm caused by the beta blocker
c. inhibition of electrical current in the retina caused by
ivabradine
d. all of the above

8. The addition of avibactam to ceftazidime improves its activity
against:
a. Pseudomonas aeruginosa
b. methicillin-resistant Staphylococcus aureus
c. Streptococcus pneumoniae
d. all of the above

4. Ivabradine has not been shown to:
a. cause atrial fibrillation
b. reduce cardiovascular mortality
c. cause fetal toxicity in animals
d. all of the above
Fluticasone Furoate (Arnuity Ellipta) for Asthma
5. The most effective long-term treatment for control of persistent
asthma is:
a. an inhaled corticosteroid
b. an inhaled long-acting beta2-agonist
c. montelukast
d. an inhaled long-acting anticholinergic

Ceftazidime/Avibactam (Avycaz) – A New Intravenous Antibiotic

9. Avycaz is the first beta-lactam/beta-lactamase inhibitor to
have activity against:
a. Methicillin-resistant Staphylococcus aureus
b. Bacteroides fragilis
c. Metallo-beta-lactamase producing Acinetobacter
baumannii
d. Klebsiella pneumoniae carbapenemase-producing
Enterobacteriaceae
10. FDA approval of Avycaz was based on:
a. the established efficacy of ceftazidime alone for treatment
of complicated UTI and intra-abdominal infections
b. in vitro activity of avibactam
c. two phase 2 trials
d. all of the above

ACPE UPN: Per Issue Exam: 0379-0000-15-469-H01-P; Release: May 25, 2015, Expire: May 25, 2016
Comprehensive Exam 72: 0379-0000-15-072-H01-P; Release: July 2015, Expire: July 2016

EDITOR IN CHIEF: Mark Abramowicz, M.D.; EXECUTIVE EDITOR: Gianna Zuccotti, M.D., M.P.H., F.A.C.P., Harvard Medical School; EDITOR: Jean-Marie Pflomm, Pharm.D.;
ASSISTANT EDITORS, DRUG INFORMATION: Susan M. Daron, Pharm.D., Corinne Z. Morrison, Pharm.D., Michael P. Viscusi, Pharm.D.; CONSULTING EDITORS: Brinda M. Shah, Pharm.D.,
F. Peter Swanson, M.D; SENIOR ASSOCIATE EDITOR: Amy Faucard
CONTRIBUTING EDITORS: Carl W. Bazil, M.D., Ph.D., Columbia University College of Physicians and Surgeons; Vanessa K. Dalton, M.D., M.P.H., University of Michigan Medical
School; Eric J. Epstein, M.D., Albert Einstein College of Medicine; Jane P. Gagliardi, M.D., M.H.S., F.A.C.P., Duke University School of Medicine; Jules Hirsch, M.D., Rockefeller
University; David N. Juurlink, BPhm, M.D., Ph.D., Sunnybrook Health Sciences Centre; Richard B. Kim, M.D., University of Western Ontario; Hans Meinertz, M.D., University Hospital,
Copenhagen; Franco M. Muggia, M.D., New York University Medical Center; Sandip K. Mukherjee, M.D., F.A.C.C., Yale School of Medicine; Dan M. Roden, M.D., Vanderbilt University
School of Medicine; Esperance A.K. Schaefer, M.D., M.P.H., Harvard Medical School; F. Estelle R. Simons, M.D., University of Manitoba; Neal H. Steigbigel, M.D., New York
University School of Medicine; Arthur M. F. Yee, M.D., Ph.D., F.A.C.R., Weill Medical College of Cornell University
MANAGING EDITOR: Susie Wong; ASSISTANT MANAGING EDITOR: Liz Donohue; EDITORIAL ASSISTANT: Cheryl Brown

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